Significance HIV is a sexually transmitted disease and a vaccine capable of preventing sexual transmission of HIV should elicit mucosal immune responses in the genital tract. Objectives To determine if the transient viremia and immune response that occurs after intravaginal (IVAG), intravenous (IV) or intranasal (IN) inoculation with SHIV 89.6, could confer protection from IVAG SIV challenge, the SHIV 89.6 infected/exposed animals were challenged intravaginally with SIVmac 239. Results Three of 3 IVAG immunized animals, 4 of 6 IN immunized animals and 3 of 6 IV immunized animals were protected from SIV239 challenge. Detailed studies of the immune responses in these animals demonstrated that the protection occurs despite the absence of SIV-specific IgA in vaginal secretions. The protection apparently did not require the presence of immune responses to highly variable regions of the viral envelope. The protection occurred only in animals that had been infected with the SHIV for more than 28 weeks before the SIV challenge. This result clearly demonstrates that the route of immunization effects the level of protection from IVAG challenge with pathogenic SIV. Eighteen additional animals have been immunized with SHIV 89.6 (6 by IVAG route, 6 by IV route and 6 by IN route). These animals will be challenged by IVAG inoculation with SIVmac 239 shortly. Future Directions We are continuing to monitor the animals to document differences in clinical outcome. We are designing studies to identify the protective immune responses in the SHIV-immunized animals. We will then develop vaccines which can elicit similar immune responses when administered by the appropriate route. KEY WORDS vaccine protection, mucosal immunity, SIV vaginal transmission FUNDING NIH Grants AI35545 and AI44480 PUBLICATIONS Lu, X, H. Kiyono, D. Lu, S. Kawabata, J. Torten, S. Srinivasan, P.J. Dailey, J.R. McGhee, T. Lehner, C.J. Miller. Targeted lymph node immunization with whole-inactivated SIV or envelope and core subunit antigen vaccines does not reliably protect rhesus macaques from vaginal challenge with SIVmac251. AIDS. 12:1-10. 1998. McChesney M.B., J. R. Collins, D. Lu, X. Lu, J. Torten, R. L. Ashley, M. W. Cloyd, C. J. Miller. Occult Systemic Infection and Persistent SIV-Specific CD4+ T Cell Proliferative Responses in Rhesus Macaques that Were Transiently Viremic after Intravaginal Inoculation of SIV. J. Virology 72:10029-10035, 1998.